RELMalpha-expressing macrophages mediate host disease tolerance in mucosal infection

RELMα表达巨噬细胞介导粘膜感染中宿主疾病耐受性

• 批准号: 10028145
• 负责人: Meera Goh Nair
• 金额: $ 66.85万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028145
• 关键词: 3-Dimensional; Acute; Address; Adoptive Cell Transfers; Adoptive Transfer; Air; Biological Assay; Biology; Blocking Antibodies; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cells; Cellular Structures; Chimera organism; Chimeric Proteins; Coculture Techniques; Complement; Data; Disease; Epithelial Cells; Equilibrium; Gene Expression; Helminths; Hematopoietic; Heterogeneity; Hookworm Infections; Hookworms; Human; Immune; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory; Injury; Integrins; Knockout Mice; Liquid substance; Lung; Lung Inflammation; Measures; Mediating; Mesenchymal Stem Cells; Migration Assay; Mucous Membrane; Mus; Nippostrongylus; Parasites; Pathogenicity; Pathologic; Pathology; Pathway interactions; Proteins; Public Health; Reagent; Recovery; Regulation; Reporter; Resolution; Rodent; Signal Pathway; Signal Transduction; Soil; Stromal Cells; Structure of parenchyma of lung; System; Technology; Therapeutic; Tissues; airway epithelium; base; cytokine; design; eosinophil; experimental study; genetic signature; healing; helminth infection; immunopathology; inhibitor/antagonist; insight; lung repair; macrophage; migration; monocyte; mouse model; new therapeutic target; novel; pathogen; pathogenic microbe; public health relevance; resistin; response; scaffold; tissue injury; tissue repair; wound healing

The optimal host response to microbial pathogens requires balancing effective pathogen killing with limiting tissue pathology caused by the pathogen or by the host’s own immune response. This host disease tolerance phenomenon is especially critical in infections with helminths, which are macroparasites that can cause severe tissue damage and inflammation. Using a mouse model of hookworm infection with Nippostrongylus brasiliensis (Nb), we identify Resistin-like molecule (RELM)a as a highly secreted protein that protects the host from potentially fatal infection-induced lung tissue damage at the expense of optimal hookworm killing. Our central hypothesis is that RELMa is a host disease tolerance mechanism that shifts the balance from helminth killing to resolution of inflammation and tissue healing. RELMa is expressed by immune cells such as macrophages and non-immune cells such as epithelial cells (EC). In preliminary data utilizing bone marrow chimeras and macrophage co-cultures, we identified that RELMa- expressing alternatively activated macrophages (AAMac) are less efficient at Nb killing, but instead dampen lung inflammation and promote tissue repair. Further, we generate unique Arginase1/RELMa AAMac dual reporters, that reveal AAMac heterogeneity and implicate RELMa+ AAMacs as a new wound healing macrophage subset. Based on these findings, the focus of this proposal is to combine novel cell-specific RELMa KO/reporter mice with functional co-culture assays and new RELMa reagents to delineate RELMa function in macrophage- helminth interactions and mucosal tissue healing. In Aim 1, we will employ cell-specific RELMa KO/reporter mice and adoptive cell transfers to delineate the contribution of RELMa derived from innate cells (AAMac or eosinophils) or EC to Nb immunity and tissue healing. In Aim 2, we will investigate RELMa regulation of macrophage-Nb interaction using AAMac dual reporter mice, RELMa fusion proteins and blocking antibodies, and optimized co-culture assays. In Aim 3, we will employ 3D lung scaffold and EC air-liquid interface co-cultures with AAMacs and mesenchymal stem cells to determine how RELMa-expressing AAMacs and ECs interact with the lung stroma and aid lung tissue recovery. We anticipate that a better understanding of the beneficial versus pathogenic effects of RELMa in helminth infection could guide therapeutic strategies to enhance anti-helminth immunity while limiting pathologic inflammation and promoting tissue healing. Our findings provide new insight into alternatively activated macrophage biology and macrophage-stromal cell interactions, which could be broadly applicable to resolving mucosal tissue injury and inflammation that are of significant public health concern.

对微生物病原体的最佳宿主反应需要平衡有效的病原体杀死 通过病原体或宿主自身的免疫反应引起的限制组织病理学。 这种宿主疾病耐受现象在蠕虫感染中尤其重要， 是可能导致严重组织损伤和炎症的大型岩石。使用鼠标 钩虫感染的模型，用巴西尼西氏菌（NB），我们识别抗素样 分子（relm）A作为一种高度分泌的蛋白质，可保护宿主免受潜在致命 感染引起的肺组织损伤，牺牲了最佳的钩虫杀伤。我们的中心 假设是，Relma是一种宿主疾病的耐受性机制，它使平衡从 蠕虫杀死感染和组织愈合的杀戮。免疫表达relma 巨噬细胞和非免疫细胞等细胞，例如上皮细胞（EC）。在初步 利用骨髓嵌合体和巨噬细胞共培养的数据，我们确定 表达替代激活的巨噬细胞（AAMAC）在NB杀戮时效率较低，但 而不是该死的肺部感染并促进组织修复。此外，我们产生了独特的 Arginase1/Relma AAMAC双向报告，揭示了AAMAC异质性和隐式 Relma+ AAMACS作为一种新的伤口愈合巨噬细胞子群。基于这些发现， 该建议的重点是将新颖的细胞特异性Relma KO/报告鼠与功能相结合 共培养分析和新的Relma试剂，以描绘巨噬细胞中的相关功能 蠕虫相互作用和粘膜组织愈合。在AIM 1中，我们将采用特定细胞的关系 KO/记者小鼠和自适应细胞转移，以描绘从源自 先天细胞（AAMAC或嗜酸性粒细胞）或EC进行NB免疫学和组织愈合。在AIM 2中，我们将 使用AAMAC双重报道小鼠研究巨噬细胞-NB相互作用的Relma调节， 中级融合蛋白和阻断抗体，并优化的共培养分析。在AIM 3中，我们 将使用3D肺脚手架和EC空气界面与AAMACS和 间充质干细胞确定反对反应的AAMAC和EC如何与 肺基质和有助于肺组织恢复。我们预计，对 Rerma在蠕虫感染中的有益与致病作用可以指导治疗 在限制病理注射和 促进组织愈合。我们的发现提供了有关激活的巨噬细胞的新见解 生物学和巨噬细胞细胞相互作用，可以广泛适用于解决 粘膜组织损伤和感染与公共卫生有关。